Atropisomers of 3-heteroaryl-4(3H)-quinazolinones for the treatment of neurodegenerative and CNS-trauma related conditions

Abstract

The present invention relates to novel atropisomers of 3-heteroaryl-4(3H)-quinazolinones of the formula Ia, and their pharmaceutically acceptable salts, and pharmaceutical compositions and methods of treating neurodegenerative and CNS-trauma related conditions.

What is claimed is:  
     
       1. An atropisomer of the formula                    
       wherein each of “A, B and D” is nitrogen or —CH—, with the proviso that only one of “A”, “B” and “D” can be nitrogen; wherein n is an integer from one to four and wherein each R 5  is a substituent on any carbon atom of the “A, B, D” ring capable of supporting an additional bond, with the proviso that one R 5  must be attached to a carbon atom ortho to the asterisked carbon of the ring; wherein each R 5  may be independently selected from the group consisting of (C 1 -C 6 )alkyl and halogen;  
       R 2  is a phenyl group of the formula:                    
       R 3  is hydrogen or halo;  
       R 9  is hydrogen, halo, CF 3 , (C 1 -C 6 )alkyl optionally substituted with one to three halogen atoms, (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms, (C 1 -C 6 )alkylthiol, amino-(CH 2 ) s —, (C 1 -C 6 )alkyl-NH—(CH 2 ) s —, di(C 1 -C 6 )alkyl-N—(CH 2 ) s —, (C 3 -C 7 )cycloalkyl-NH—(CH 2 ) s —, H 2 N—(C═O)—(CH 2 ) s —, (C 1 -C 6 )alkyl-HN—(C═O)—(CH 2 ) s —, di(C 1 -C 6 )alkyl-N—(C═O)—(CH 2 ) s —, (C 3 -C 7 )cycloalkyl-NH—(C═O)—(CH 2 ) s —, R 13 O—(CH 2 ) s —, R 13 O—(C═O)—(CH 2 ) s —, H(O═C)—NH—(CH 2 ) s —, (C 1 -C 6 )alkyl-(O═C)—NH—(CH 2 ) s —,                    
        H—(C═O)—(CH 2 ) s —, (C 1 -C 6 )alkyl-(C═O)—, hydroxy, hydroxy-(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-, or —CN;  
       R 10  is hydrogen or halo;  
       R 11  is selected from hydrogen, halo, CF 3 , (C 1 -C 6 )alkyl optionally substituted with one to three halogen atoms, (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms, (C 1 -C 6 )alkylthiol, amino-(CH 2 ) p —, (C 1 -C 6 )alkyl-NH—(CH 2 ) p —, di(C 1 -C 6 )alkyl-N—(CH 2 ) p —, (C 3 -C 7 )cycloalkyl-NH—(CH 2 ) p —, amino-(C 1 -C 6 )alkyl-NH—(CH 2 ) p —, (C 1 -C 6 )alkyl-NH—(C 1 -C 6 )alkyl-NH—(CH 2 ) p —, di(C 1 -C 6 )alkyl-N-(C 1 -C 6 )alkyl-NH—(CH 2 ) p —,                    
        H 2 N—(C═O)—(CH 2   p —, (C 1 -C 6 )alkyl-HN—(C═O)—(CH 2 ) p —, di(C 1 -C 6 )alkyl-N—(C═O)—(CH 2 ) p , (C 3 -C 7 )cycloalkyl-NH—(C═O)—(CH 2 ) p —, R 13 O—(CH 2 ) p —, R 13 O—(C═O)—(CH 2 ) p —, H(O═C)—O—, H(O═C)—O—(C 1 -C 6 )alkyl-, H(O═C)—NH—(CH 2 ) p —, (C 1 -C 6 )alkyl-(O═C)—NH—(CH 2 ) p —, —CHO, H—(C═O)—(CH 2 ) p —, (C 1 -C 6 )alkyl-(C═O)—(CH 2 ) p —,                    
        (C 1 -C 6 )alkyl-(C═O)—O—(CH 2 ) p —, amino-(C 1 -C 6 )alkyl-(C═O)—O—(CH 2 ) p —, (C 1 -C 6 )alkyl-(C═)—O—(CH 2 ) p —, amino-(C 1 -C 6 )alkyl-(C═O)—O—(CH 2 ) p —, (C 1 -C 6 )alkyl-(C═O)—O—(CH 2 ) p —,  
        (C 1 -C 6 )alkyl-NH—(C 1 -C 6 )alkyl-(C═O)—O—(CH 2 ) p —, di(C 1 -C 6 )alkyl-N—(C 1 -C 6 )alkyl-(C═O)—O—(CH 2 ) p —, amino-(C 1 -C 6 )alkyl-O—(C═O)—(CH 2 ) p —, (C 1 -C 6 )alkyl-NH—(C 1 -C 6 )alkyl-O—(C═O)—(CH 2 ) p —, di(C 1 -C 6 )alkyl-N—(C 1 -C 6 )alkyl-O—(C═O)—(CH 2 ) p —, hydroxy, hydroxy-(C 1 -C 6 )alkyl-, hydroxy-(C 1 -C 6 )alkyl-NH—(CH 2 ) p —, (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-, —CN, piperidine-(CH 2 ) p —, pyrrolidine-(CH 2 ) p —, and 3-pyrroline-(CH 2 ) p —, wherein said piperidine, pyrrolidine and 3-pyrroline moieties of said piperidine-(CH 2 ) p —, pyrrolidine-(CH 2 ) p — and 3-pyrroline-(CH 2 ) p — groups may optionally be substituted on any of the ring carbon atoms capable of supporting an additional bond, with zero to two substituents, with a substituent independently selected from halo, CF 3 , (C 1 -C 6 )alkyl optionally substituted with one to three halogen atoms, (C 1 -C 6 )alkoxy optionally substituted with one to three halogen atoms, (C 1 -C 6 )alkylthiol, amino-(CH 2 ) p —, (C 1 -C 6 )alkyl-NH—(CH 2 ) p —, di(C 1 -C 6 )alkyl-N—(CH 2 ) p —, (C 3 -C 7 )cycloalkyl-NH—(CH?) p —, amino-(C 1 -C 6 )alkyl-NH—(CH 2 ) p —, (C 1 -C 6 )alkyl-NH—(C 1 -C 6 )alkyl-NH-CH 2 ) p —, di(C 1 -C 6 )alkyl-N—(C 1 -C 6 )alkyl-NH—(CH 2 ) p —, (C 1 -C 6 )alkyl—O—(C 1 -C 6 )alkyl-,                    
        H 2 N(C═O)—(CH 2 ) p —, (C 1 -C 6 )alkyl-HN—(C═O)—(CH 2 ) p —, di(C 1 -C 6 )alkyl-N—(C═O)—(CH 2 ) p , (C 3 -C 7 )cycloalkyl-NH—(C═O)—(CH 2 ) p —, R 13 O—(CH 2 ) p —, R 13 )—(C═O)—(CH 2 ) p —, H(O═C)—O—, H(O═C)—O—(C 1 -C 6 )alkyl-, H(O═C)—NH—(CH 2 ) p —, (C 1 -C 6 )alkyl-(O═)NH—(CH 2 ) p —, —CHO, H—(C═O)—(CH 2 ) p —, (C 1 -C 6 )alkyl-(C═O)—,                    
        (C 1 -C 6 )alkyl-(C═O)—O—NH—(CH 2 ) p —, amino-(C 1 -C 6 )alkyl-(C═O)—O—(CH 2 ) p —, (C 1 -C 6 )alkyl-NH—(C 1 -C 6 )alkyl-(C═O)—O—(CH 2 ) p —, di(C 1 -C 6 )alkyl-N—(C 1 -C 6 )alkyl-(C═O)—O—(CH 2 ) p —, hydroxy, hydroxy-(C 1 -C 6 )alkyl-, hydroxy-(C 1 -C 6 )alkyl-NH—(CH 2 ) p —, and —CN;  
       R 12  is hydrogen, —CN or halo;  
       each p is independently an integer from zero to 4; and  
       s is an integer from zero to 4;  
       wherein the dashed bond represents a double bond;  
       or the pharmaceutically acceptable salts of such compounds. 
     
     
       2. A compound according to  claim 1  wherein R 3  is hydrogen, halo or (C 1 -C 6 )alkyl. 
     
     
       3. The compound according to  claim 1  wherein “B” is nitrogen, “A” and “D” are carbon and R 3  is hydrogen. 
     
     
       4. A compound according to  claim 1  wherein R 5  is chloro or methyl. 
     
     
       5. A compound according to  claim 3  wherein n is one and R 5  is a substituent ortho to the asterisked carbon. 
     
     
       6. The compound according to  claim 1  wherein R 9  is fluoro, chloro, —CN or hydroxy; or R 11  is —CHO, chloro, fluoro, methyl, (C 1 -C 6 )alkyl-NH—(CH 2 ) p —, di(C 1 -C 6 )alkyl-N—(CH 2 ) p —, or cyano. 
     
     
       7. The compound according to  claim 2  wherein R 9  is fluoro, chloro, —CN or hydroxy; or R 11  is —CHO, chloro, fluoro, methyl, (C 1 -C 6 )alkyl-NH—(CH 2 ) p —, di(C 1 -C 6 )alkyl-N—(CH 2 ) p —, or cyano. 
     
     
       8. A compound according to  claim 1  wherein R 2  is heteroaryl and said heteroaryl is either an six-membered heterocycle wherein “K”, “L” and “M” are carbon, or “K” and “L” are carbon and “M” is nitrogen, or said heteroaryl is an five membered heterocycle wherein “T” is nitrogen, “P” is sulfur and “Q” is carbon, or “T” is nitrogen or sulfur, “Q” is nitrogen or sulfur and “P” is carbon or “T” is oxygen and “P” and “Q” are each carbon. 
     
     
       9. The compound according to  claim 1  wherein said compound is selected from the group consisting of: 
       (S)-6-fluoro-2-[2-(2-fluoro-phenyl)-vinyl-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one;  
       (S)-2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-benzonitrile;  
       (S)-2-{2-[6-fluoro-3-(2-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-vinyl}-benzonitrile;  
       (S)-2-{(2-chloro-pyridin-3-yl)-6-fluoro-4-oxo-3,4-dihydroquinazol-in-2-yl]-vinyl}-benzonitrile;  
       (S)-2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2yl]-vinyl}-4-methyl-benzonitrile;  
       (S)-2-[2-(5-diethylaminomethyl-2-fluoro-phenyl)-vinyl]-6-fluoro-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one, or  
       (S)-6-fluoro-2-[2-(2-fluoro-5-pyrrolidin-1-ylmethyl-phenyl)-vinyl]-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one.  
     
     
       10. A pharmaceutical composition for treating a condition selected from epilepsy and convulsions, in a mammal, comprising an amount of a compound according to  claim 1  effective in treating such condition and a pharmaceutically acceptable carrier. 
     
     
       11. A method for treating a condition selected from epilepsy and convulsions, in a mammal, comprising administering to a mammal requiring such treatment an amount of a compound according to  claim 1  effective in treating such condition. 
     
     
       12. A pharmaceutical composition for treating a condition selected from epilepsy and convulsions, in a mammal, comprising an AMPA receptor antagonizing effective amount compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       13. A method for treating a condition selected from epilepsy and convulsions, in a mammal, comprising administering to a mammal requiring such treatment an AMPA receptor antagonizing effective amount of a compound according to  claim 1 .